Metabolic interactions between tumor cells and the immunce system in GBM A potential Achilles heel of GBM for novel therapeutics
GBM 中肿瘤细胞与免疫系统之间的代谢相互作用是 GBM 新疗法的潜在致命弱点
基本信息
- 批准号:10673172
- 负责人:
- 金额:$ 41.7万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-08-01 至 2027-07-31
- 项目状态:未结题
- 来源:
- 关键词:AffectApolipoprotein EBiologyBrain NeoplasmsC57BL/6 MouseCell CommunicationCell CompartmentationCell CycleCell LineageCell ShapeCell physiologyCellsCellular Metabolic ProcessCellular biologyClinicalCommunicationComplexCoupledDependenceDiseaseDisease OutcomeDisease ProgressionEnvironmentExhibitsFABP3 geneFatty AcidsFlow CytometryGeneticGlioblastomaGliomaGlucoseGoalsGrowthHeterogeneityImageImmuneImmune checkpoint inhibitorImmune systemImmunological ModelsIn VitroInduction of ApoptosisInterventionInvestigationKnockout MiceLCN2 geneLabelLaboratoriesLinkLipidsLogicMacrophageMaintenanceMalignant NeoplasmsMediatingMetabolicMitochondriaModelingMolecularMorbidity - disease rateMusMyeloid-derived suppressor cellsNatureOutcomeOxidative PhosphorylationPathway interactionsPatientsPhenotypePlayPopulationProliferatingRecurrenceRecurrent diseaseRegulatory T-LymphocyteReportingResearch DesignResistanceRoleShapesSignal TransductionSortingSpecimenSystemT-LymphocyteTechnologyTestingTherapeuticTherapeutic EffectTimeTransgenic MiceTranslatingTumor ImmunityTumor PromotionWorkadipokinesaerobic glycolysisanti-PD1 therapyatorvastatincancer cellcancer therapychemotherapyclinically relevantcomparativecytokinedigitalexperimental studygenomic profilesimmune cell infiltrateimprovedin vivoinsightintercellular communicationlipid biosynthesislipid metabolismlipid transportmortalityneoplastic cellnovel therapeuticspharmacologicprogramsrecruitsingle-cell RNA sequencingstandard of caretemozolomidetherapeutic evaluationtherapy resistanttranscriptomicstumortumor heterogeneitytumor microenvironmenttumor progressiontumor-immune system interactionstumorigenicuptake
项目摘要
ABSTRACT
Background: We recently revealed that glioblastoma (GBM) contain cell populations with distinct metabolic
requirements, with fast-cycling cells (FCCs) harnessing aerobic glycolysis, and treatment-resistant slow-cycling
cells (SCCs) preferentially engaging lipid metabolism. How the different tumor cells interact with immune cells
and how this metabolic heterogeneity shapes the immune landscape in GBM has yet to be understood.
Objectives/Hypothesis: The objectives of this study are to understand the mechanisms of communication in
the tumor microenvironment, specifically to characterize the metabolic interactions between SCCs (a
therapeutically resistant population that drive disease progression and recurrence) and the immune compartment.
Here, we will investigate a model of intercellular communication within GBM where SCCs shape an
immunosuppressive tumor milieu, which in turn assume metabolic support to SCCs by providing them with lipids,
which are essential for SCC metabolism and function. Importantly, we will test multiple genetic and clinically
amenable pharmacological approaches disrupting this metabolic interplay to antagonize GBM.
Specific aims: Our specific aims will be 1) Dissect the relationship of SCCs with the tumor microenvironment,
2) Delineate how recruited immune suppressive cell mediate SCC-driven tumor progression, and 3) Establish
that immune infiltrates provide metabolic support to SCCs by providing lipids.
Study design: The link between tumor heterogeneity and tumor immune landscape in GBM will be deciphered
with specific investigations of the metabolic interplay taking place between these cellular compartments.
In aim 1, we will delineate the cell lineage (SCC vs FCC) relationship with immune infiltrates by investigating
their genomic profile and spatial organization, using single cell RNA sequencing technology and GeoMx Digital
Spatial Profiling, respectively. We will also evaluate the role of the specific adipokine, Lipocalin-2, in shaping the
immune microenvironment. In aim 2 we will employ multiple approaches disrupting the macrophage, myeloid-
derived suppressor cell, and regulatory T cell compartments, and compare the effect on survival, growth and
chemotherapy sensitivity of SCCs and FCCs. In aim 3 the use of fluorescently labeled lipids combined with flow
cytometry and time lapse imaging will enable the comparison of lipid transfer between immune cells, FCCs and
SCCs. Finally, in vivo experiments will test the hypothesis that targeting lipid trafficking (inhibition of FABP3 or
ApoE) or lipogenesis (statin treatment) provide therapeutic benefits by affecting SCCs and rendering the overall
tumor more responsive to chemotherapy. Based on the recently reported synergistic effect of statins with immune
checkpoint inhibitors, we will also evaluate the combination of statins with anti PD-1 therapy.
Impact: Successfully completed, this project will validate therapeutically amenable approaches targeting
metabolic communication to improve brain tumor associated morbidity and mortality.
摘要
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Loic Pierre Deleyrolle其他文献
Loic Pierre Deleyrolle的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Loic Pierre Deleyrolle', 18)}}的其他基金
Optimizing CAR T therapy via metabolic engineering for thetreatment of GBM
通过代谢工程优化 CAR T 疗法治疗 GBM
- 批准号:
10722922 - 财政年份:2023
- 资助金额:
$ 41.7万 - 项目类别:
Metabolic interactions between tumor cells and the immunce system in GBM A potential Achilles heel of GBM for novel therapeutics
GBM 中肿瘤细胞与免疫系统之间的代谢相互作用是 GBM 新疗法的潜在致命弱点
- 批准号:
10522529 - 财政年份:2022
- 资助金额:
$ 41.7万 - 项目类别:
Slow cycling cell RNA based T cell therapy to prevent recurrence in GBM
基于慢循环细胞 RNA 的 T 细胞疗法可预防 GBM 复发
- 批准号:
10331046 - 财政年份:2021
- 资助金额:
$ 41.7万 - 项目类别:
相似海外基金
Role of human apolipoprotein E isoforms in long-term effects of West Nile Virus exposure on Alzheimer's disease-related behavioral alteration, cognitive injury, neuroinflammation, and neuropathology
人类载脂蛋白 E 同工型在西尼罗河病毒暴露对阿尔茨海默病相关行为改变、认知损伤、神经炎症和神经病理学的长期影响中的作用
- 批准号:
10658408 - 财政年份:2023
- 资助金额:
$ 41.7万 - 项目类别:
A Therapeutic Role for Apolipoprotein-E in the Germ Theory of Alzheimer's Dementia
载脂蛋白-E 在阿尔茨海默氏痴呆病菌理论中的治疗作用
- 批准号:
10601779 - 财政年份:2023
- 资助金额:
$ 41.7万 - 项目类别:
Investigating how apolipoprotein E genotypes modify fatty acid metabolism
研究载脂蛋白 E 基因型如何改变脂肪酸代谢
- 批准号:
RGPIN-2018-06116 - 财政年份:2022
- 资助金额:
$ 41.7万 - 项目类别:
Discovery Grants Program - Individual
Targeting apolipoprotein E for Alzheimer's disease therapy.
靶向载脂蛋白 E 治疗阿尔茨海默病。
- 批准号:
22K06460 - 财政年份:2022
- 资助金额:
$ 41.7万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The role of apolipoprotein E in Alzheimer's adaptive immunity
载脂蛋白E在阿尔茨海默病适应性免疫中的作用
- 批准号:
10674878 - 财政年份:2022
- 资助金额:
$ 41.7万 - 项目类别:
Apolipoprotein E and immunometabolism in Alzheimer's disease
载脂蛋白 E 和阿尔茨海默病的免疫代谢
- 批准号:
10388528 - 财政年份:2022
- 资助金额:
$ 41.7万 - 项目类别:
The role of apolipoprotein E in Alzheimer's adaptive immunity
载脂蛋白E在阿尔茨海默病适应性免疫中的作用
- 批准号:
10515592 - 财政年份:2022
- 资助金额:
$ 41.7万 - 项目类别:
Apolipoprotein E and immunometabolism in Alzheimer's disease
载脂蛋白 E 与阿尔茨海默病的免疫代谢
- 批准号:
10644996 - 财政年份:2022
- 资助金额:
$ 41.7万 - 项目类别:
Apolipoprotein E glycosylation and its role in Alzheimer's disease pathogenesis
载脂蛋白E糖基化及其在阿尔茨海默病发病机制中的作用
- 批准号:
10601040 - 财政年份:2021
- 资助金额:
$ 41.7万 - 项目类别:
Impact of cysteine modifications of apolipoprotein E on the remnant lipoprotein metabolism
载脂蛋白E半胱氨酸修饰对残余脂蛋白代谢的影响
- 批准号:
21K07310 - 财政年份:2021
- 资助金额:
$ 41.7万 - 项目类别:
Grant-in-Aid for Scientific Research (C)